Human cystic hydatidosis due to Echinococcus granulosus larva is a serious public health problem in many parts of the world. The disease is highly endemic in Libya, previous studies concentrated on north-east, central and north-west areas of the country. This study determined sero-prevalence and exposure rates of Echinococcus granulosus infection in Southern Libya. This household community-based cross-sectional study was carried in Murzuk province in southern Libya during the period January 2004 to July 2005. Following informed consent, 1274 individuals from 25 villages were randomly recruited. Interviews, serologic screening and biochemical profiles were carried out. Demographic, clinical and laboratory data were collected, entered, checked and verified using the EpiInfo2004 software. Twenty nine individuals (29/1274; 2.3%) were sero-reactive, sero-prevalence rates were significantly variable among different areas [range 1.9% to 4.1%; p=0.0006]. Males were significantly more sero-reactive compared to females [p=0.008]. Individuals in the age group 7-50 years were more affected compared to other age groups (p=0.006). Sero-reactive individuals had serum urea, creatinine and bilirubin within reference ranges. AST, ALT and alkaline phosphatase liver enzymes were universally increased (p=0.0000). The exposure rate to Echinococcus granulosus was calculated as 6.8%. Echinococcus granulosus infection is prevalent in southern Libya with an exposure rate of 6.8%.